Hepatocellular carcinoma(HCC)is the most common primary liver tumor and the third leading cause of cancer-related mortality globally.The phosphatidylinositol-3 kinase(PI3K)/protein kinase B(AKT)/mammalian target of ra...Hepatocellular carcinoma(HCC)is the most common primary liver tumor and the third leading cause of cancer-related mortality globally.The phosphatidylinositol-3 kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)signaling pathway is critically involved in HCC pathogenesis,stimulating uncontrolled cell proliferation,survival,and tumor progression.The overactivation of this pathway is strongly linked to poor prognosis,making it a crucial target for therapeutic intervention.The oncogenic roles of PI3K/AKT/mTOR components in HCC have been highlighted,noting that class I PI3K deregulation,phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA)upregulation,and mTOR overexpression could be associated with poor HCC outcomes.To the best of our knowledge,this is the first time that the clinical trials investigating PI3K/AKT/mTOR inhibitors in HCC are analyzed.Accordingly,there is a predominance of mTOR inhibitors,with everolimus being the most frequently utilized drug.However,only 10%of studies advanced to phase III or IV,predominantly involving mTOR inhibitors.Challenges such as adverse events like hyperglycemia and bone marrow suppression,as well as the emergence of treatment resistance,have hindered the success of these therapies.Combination therapies,particularly those involving mitogen-activated protein kinase kinase(MEK)inhibitors,chemotherapy,immune checkpoint inhibitors,and vascular endothelial growth factor(VEGF)inhibitors,have shown promise in overcoming these challenges.Recent advances in nanotechnology offer the potential for improving drug delivery and reducing toxicity.展开更多
Pathogenesis of chronic myeloid leukemia(CML)has mostly been studied with regard to the oncogenic role of BCR/ABL fusion,however,recent disclosures have declared that the challenges with the treatment of CML patients ...Pathogenesis of chronic myeloid leukemia(CML)has mostly been studied with regard to the oncogenic role of BCR/ABL fusion,however,recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored.Given the involvement of cyclin-dependent kinases(CDKs)in the pathogenesis of CML,the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells.Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27.The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity,suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor,at least partly,through a c-Mycdependent mechanism.To the best of our knowledge,to date,no study has addressed the effect of autophagy on CML cell response to AT7519,and,herein,we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562.Overall,we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.展开更多
Background:Despite progress in therapeutic strategies,treatment failure in hepatocellular carcinoma(HCC)remains a major challenge,resulting in low survival rates.The presence of bacteria and the host’s immune respons...Background:Despite progress in therapeutic strategies,treatment failure in hepatocellular carcinoma(HCC)remains a major challenge,resulting in low survival rates.The presence of bacteria and the host’s immune response to bacteria can influence the pathogenesis and progression of HCC.We developed a risk model based on bacterial response-related genes(BRGs)using gene sets from molecular signature databases to identify new markers for predicting HCC outcomes and categorizing patients into different risk groups.Methods:The data from the Cancer Genome Atlas(TCGA)portal was retrieved,and differentially expressed BRGs were identified.Uni-and multivariate Cox regression and least absolute shrinkage and selection operator(LASSO)LASSO analyses were executed to develop the prognostic risk model.Key contributor to the prognostic model was identified,and the results were tested by using experimental assays in HCC cell lines.Results:Multivariate analysis demonstrated an independent prognostic factor of 12-BRG signature in HCC patients.The low-risk group had better overall survival with significantly lower tumor mutation burden(TMB).The risk scores were negatively correlated with the presence of tumor-infiltrating immune cells.In an effort to find the key contributor of the 12-BRG signature,we found polo like kinase1(PLK1)had the best accuracy with 1-,3-,and 5-year AUC of 0.72,0.66,and 0.65,respectively.Both PLK1 inhibitor Volasertib and the knockdown of the PLK1 gene resulted in diminished viability in HCC cell lines.The combination of PLK1 inhibition with low-dose chemotherapy exhibited an amplified effect of the treatment.Conclusion:To date,there have been no reports of BRG biomarkers in HCC,and this study represents for the first time that a 12-BRG signature has the potential to predict the survival of HCC.展开更多
文摘Hepatocellular carcinoma(HCC)is the most common primary liver tumor and the third leading cause of cancer-related mortality globally.The phosphatidylinositol-3 kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)signaling pathway is critically involved in HCC pathogenesis,stimulating uncontrolled cell proliferation,survival,and tumor progression.The overactivation of this pathway is strongly linked to poor prognosis,making it a crucial target for therapeutic intervention.The oncogenic roles of PI3K/AKT/mTOR components in HCC have been highlighted,noting that class I PI3K deregulation,phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA)upregulation,and mTOR overexpression could be associated with poor HCC outcomes.To the best of our knowledge,this is the first time that the clinical trials investigating PI3K/AKT/mTOR inhibitors in HCC are analyzed.Accordingly,there is a predominance of mTOR inhibitors,with everolimus being the most frequently utilized drug.However,only 10%of studies advanced to phase III or IV,predominantly involving mTOR inhibitors.Challenges such as adverse events like hyperglycemia and bone marrow suppression,as well as the emergence of treatment resistance,have hindered the success of these therapies.Combination therapies,particularly those involving mitogen-activated protein kinase kinase(MEK)inhibitors,chemotherapy,immune checkpoint inhibitors,and vascular endothelial growth factor(VEGF)inhibitors,have shown promise in overcoming these challenges.Recent advances in nanotechnology offer the potential for improving drug delivery and reducing toxicity.
基金the grant number:15425 from Shahid Beheshti University of Medical Sciences(Tehran,Iran)(http://en.sbmu.ac.ir/)achieved byD.B.Conflicts of Interest:The authors declare that they have no conflicts of interest to report regarding the present study.
文摘Pathogenesis of chronic myeloid leukemia(CML)has mostly been studied with regard to the oncogenic role of BCR/ABL fusion,however,recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored.Given the involvement of cyclin-dependent kinases(CDKs)in the pathogenesis of CML,the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells.Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27.The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity,suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor,at least partly,through a c-Mycdependent mechanism.To the best of our knowledge,to date,no study has addressed the effect of autophagy on CML cell response to AT7519,and,herein,we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562.Overall,we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.
文摘Background:Despite progress in therapeutic strategies,treatment failure in hepatocellular carcinoma(HCC)remains a major challenge,resulting in low survival rates.The presence of bacteria and the host’s immune response to bacteria can influence the pathogenesis and progression of HCC.We developed a risk model based on bacterial response-related genes(BRGs)using gene sets from molecular signature databases to identify new markers for predicting HCC outcomes and categorizing patients into different risk groups.Methods:The data from the Cancer Genome Atlas(TCGA)portal was retrieved,and differentially expressed BRGs were identified.Uni-and multivariate Cox regression and least absolute shrinkage and selection operator(LASSO)LASSO analyses were executed to develop the prognostic risk model.Key contributor to the prognostic model was identified,and the results were tested by using experimental assays in HCC cell lines.Results:Multivariate analysis demonstrated an independent prognostic factor of 12-BRG signature in HCC patients.The low-risk group had better overall survival with significantly lower tumor mutation burden(TMB).The risk scores were negatively correlated with the presence of tumor-infiltrating immune cells.In an effort to find the key contributor of the 12-BRG signature,we found polo like kinase1(PLK1)had the best accuracy with 1-,3-,and 5-year AUC of 0.72,0.66,and 0.65,respectively.Both PLK1 inhibitor Volasertib and the knockdown of the PLK1 gene resulted in diminished viability in HCC cell lines.The combination of PLK1 inhibition with low-dose chemotherapy exhibited an amplified effect of the treatment.Conclusion:To date,there have been no reports of BRG biomarkers in HCC,and this study represents for the first time that a 12-BRG signature has the potential to predict the survival of HCC.
